BioWorld International Correspondent

LONDON - Korean researchers working on a DNA vaccine for tuberculosis have shown that it can block subsequent activation of dormant bacteria in mice and prevent later reinfection.

The vaccine was given during infection and can be given at the same time as conventional drugs. It might provide a treatment for multidrug-resistant tuberculosis, which is untreatable and has a 50 percent fatality rate.

Youngchul Sung, of the Pohang University of Science and Technology in Kyungbuk, Republic of Korea, told BioWorld International that he and his colleagues are working on toxicology studies in preparation for seeking FDA approval.

Sung said: "We hope we can obtain funds to carry out clinical trials in the near future. I am planning to recruit Korean patients with multidrug-resistant tuberculosis and ordinary tuberculosis to these trials. If sponsors are forthcoming and the trials can go ahead soon, a DNA vaccine against tuberculosis for use in humans could be available after about four to five years."

Commenting on the study, Doug Lowrie, a senior scientist for the UK Medical Research Council, told BioWorld International: "One important aspect of this study is that it has shown for the first time that it is possible to raise an immune response that is a stage better than that to BCG, and better than the body's own response to Mycobacterium tuberculosis. Previously, no one was sure that this was achievable."

Lowrie said the Korean team had found a "remarkably high" level of protection against re-infection in mice challenged with Mycobacterium tuberculosis more than a year after their initial infection. "This is the first time this has been seen in an animal model," he said.

The work is reported in Gene Therapy (advance online publication Feb. 3) titled "Protective effect of DNA vaccine during chemotherapy on reactivation and reinfection of Mycobacterium tuberculosis."

Sung and his colleagues described how they selected genes encoding two antigens from M. tuberculosis for inclusion in the vaccine. Both are expressed on the surface of infected macrophages, one early in the course of infection and the other being more abundantly expressed during late infection. The two genes were engineered into bacterial plasmid DNA and attached to promoters that allow their expression in eukaryotic cells.

The team used a mouse model of tuberculosis in which the animals were infected by an aerosol of bacteria into the lungs. The infected mice were treated with isoniazid and pyrazinamide, and after two weeks were divided into two groups. One group received an intramuscular injection of the DNA vaccine while the other did not. BCG was not included as a control vaccine because the antibiotics would have killed it.

The results showed that control mice, which received only chemotherapy, relapsed with tuberculosis infection after several weeks. Control mice also were susceptible to later reinfection, again by an aerosol of bacteria into the lung, 66 weeks after primary infection. However, mice treated with both chemotherapy and the DNA vaccine did not relapse due to activation of latent bacteria and resisted a subsequent infectious challenge.

Lowrie, who developed the first DNA vaccine to protect against tuberculosis in 1994, said the concept had stimulated great interest from researchers in Southeast Asia. Provided DNA vaccines could be proved clinically useful, they could be easily and cheaply produced. Trials of DNA vaccines that aimed to protect against influenza, HIV, the herpes virus, the hepatitis B virus and malaria had all shown that the approach seemed safe. But research now is focused on improving the delivery, function and expression of the vaccines, in order to boost efficacy.

The paper by Sung and his colleagues, Lowrie added, is exciting because it suggests that using the DNA vaccine in conjunction with chemotherapy could reduce the length of time for which patients need to take drugs. That stands at six to nine months, but because patients quickly feel better and often stop taking the drugs, drug-resistant strains of M. tuberculosis are fostered.

"One-third of the world's population is infected with tuberculosis, yet we have made no impact on the global position of tuberculosis for many years despite what appears to be highly effective chemotherapy," Lowrie concluded. "If we could reduce the duration that someone has to take chemotherapy for, that would be a tremendous step forward."

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